The preclinical discovery and development of paliperidone for the treatment of schizophrenia.

: Paliperidone is approved in the United States and Europe for the short- and long-term treatment of schizophrenia in adults and adolescents as well as for the acute treatment of schizoaffective disorder either as monotherapy or adjunctive therapy to mood stabilizers and/or antidepressants. It is recommended in patients with hepatic impairment and evokes less drug-drug interactions.: This review article focuses on the preclinical discovery of paliperidone, the major active metabolite of risperidone. It provides details regarding paliperidone's pharmacological and neurochemical mechanisms, and their contribution to therapeutic benefits and adverse effects, based on the available literature with respect to the preclinical and clinical findings and product labels.: Paliperidone exhibits a high affinity and antagonistic activity toward D and 5-HT receptors, followed by 5-HT, H, α and α receptors. In preclinical studies, paliperidone produces antidepressant, anxiolytic, mood-stabilizing, analgesic actions, and affects the endocannabinoid system. It is also known to evoke procognitive, antioxidant, and anti-inflammatory activities. Its positive activity on neurogenesis, neuronal, and synaptic plasticity deserves to be emphasized. The clinical superiority of paliperidone is based primarily on the available formulations of the drug rather than in the subtle differences in its pharmacokinetic/pharmacodynamic properties compared to risperidone.